This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Development of safe, effective vaccines for protection against smallpox is an important component of national readiness in biodefense. The specific aims are to 1) establish the safety and clinical side effect profile of Imvamune Vaccine as compared to placebo and to Dryvax. 2) Understand the different components of the immune system that the vaccine activates to develop an immune response. 3) Understand the timing of protection in individuals receiving Imvamune in different doses and /or Dryvax for use in eventual development of recommendations in a post-event scenario for biodefense. In July, 2007, enrollment was halted at the request of CBER. The protocol has been modified as follows. One hundred and ninety-five subjects will be randomly assigned to one of three groups to be immunized twice with IMVAMUNE[unreadable] vaccine or placebo subcutaneously in Groups A and B, or to receive a single immunization with IMVAMUNE[unreadable] or placebo subcutaneously in Group F. (NOTE: A total of 197 subjects will be randomly assigned to Groups A, B, and F as two subjects were previously enrolled in Group B.) These individuals will come for follow up visits frequently in the month following vaccine, and then 6 and 12 months after receiving the first dose of vaccine. They will be asked to maintain a diary of side effects and will have lab studies done to evaluate for safety, toxicity and immune response. An alternative smallpox vaccine with an improved safety profile and immunogenicity profile is important to the nation's ability to strategically provide biodefense.